Polyphenol proteasome inhibitors, synthesis, and methods of use

Abstract

The present invention relates to synthetic green tea derived polyphenolic compounds, their modes of syntheses, and their use in inhibiting proteasomal activity and in treating cancers. The present invention is also directed to pharmaceutical compositions useful in methods of inhibiting proteasomes and of treating cancers.

1. A composition comprising at least one compound having the structure of a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of any of the foregoing; and a pharmaceutically acceptable carrier or diluent. 
       
     
     
       2. The composition according to  claim 1 , wherein said compound has less than 100% optical purity. 
     
     
       3. The composition according to  claim 1 , wherein said compound is optically pure. 
     
     
       4. A compound having the formula B: 
       
         
           
           
               
               
           
         
         wherein R is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and acyl; X is O or NH; and wherein R 1  is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and acyl. 
       
     
     
       5. A compound having the structure of a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       6. A method for synthesizing a compound having the structure of formula B, 
       
         
           
           
               
               
           
         
       
       said method comprising:
 a) coupling a compound represented by formula IV with an acid represented by formula III: 
 
       
         
           
           
               
               
           
         
       
       to form a fully protected gallate ester, wherein R, R 3 , R 4 , and R 5  are each selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, and acyl; X is O or NH; and wherein R 1  is selected from the group selected from NH, alkyl, alkenyl. cycloalkyl, heterocycloalkyl, cycloalkcnyl, heterocycloalkenyl, aryl, and acyl. 
     
     
       7. The method of  claim 6 , wherein the synthesized compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       8. The method according to  claim 6 , wherein the acid of formula III is employed in the form of a derivative which is an acyl halide or a mixed or symmetric acid anhydride; or the acid of formula III is reacted with the compound of formula IV in the presence of a condensing reagent. 
     
     
       9. The method according to  claim 8 , wherein the derivative is an acyl halide. 
     
     
       10. The method according to  claim 9 , wherein the acyl halide is selected from the group consisting of acyl chloride, acyl bromide, and acyl iodide. 
     
     
       11. The method according to  claim 6 , wherein said coupling is carried out in the presence of a base in an inert solvent. 
     
     
       12. The method according to  claim 11 , wherein the base is selected from the group consisting of dimethylaminopyridine, pyridine, tricthylamine, and diisopropylethylamine. 
     
     
       13. The method according to  claim 11 , wherein the solvent is selected from the group consisting of dichloromethane, ether, and tetrahydrofuran. 
     
     
       14. The method according to  claim 11 , wherein the acid of formula III is reacted with the compound of formula II in the presence of a condensing agent, wherein the condensing agent is selected from the group consisting of 1,3-diisopropylcarbodiimide; 1,3-dimethylaminopropyl(3-ethyl)carbodiimide; dialkyl carbodiimide; 2-halo-1-alkyl-pyridinium halides; propane phosphonic acid cyclic anhydride; N-ethoxycarbonyl-2-ethoxy-1,2, dihydroquinoline; and dicyclohexylcarbodiimine. 
     
     
       15. The method according to  claim 11 , further comprising:
 b) deprotecting the gallate ester, wherein said deprotecting is selective or non-selective. 
 
     
     
       16. The method according to  claim 15 , wherein said deprotecting is performed with Pd(OH) 2  and H 2 .